Summary The severe acute and chronic developmental and neurological impacts of PKU seen in infants and adults are due to the presence of high concentrations of phenylalanine (Phe) in the blood. In pregnant mothers with PKU, high Phe levels significantly increase the risk of miscarriage or severe developmental disorders in the growing fetus. The adverse effects of PKU can be alleviated by lowering systemic levels of Phe, and various interventions (pharmacological, enzymatic, and diet-related) have been attempted with some success. This work is based on that hypothesis that highly active enzymes delivered by probiotic bacteria that utilize Phe as substrate can re- direct its flux away from the apical amino acid transporters in the gut and thus minimize Phe absorption in the gut. The long-term goal of this work is to develop this Altered Probiotic Therapy (APT) approach for the treatment of PKU. The objective of this proposal is to engineer the activity of a probiotic organism to deliver therapeutic Phenylalanine Ammonia Lyase (PAL) enzyme to the gut and to enhance residence time for efficient Phe depletion. The APT approach can provide a novel and holistic approach to treating the various Phe-related metabolic disorders including PKU, maternal PKU, and hyperphenylalaninemia (HPA).